Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial

Maarten Korrel; Leia R Jones; Jony van Hilst; Gianpaolo Balzano; Bergthor Björnsson; Ugo Boggi; Svein Olav Bratlie; Olivier R Busch; Giovanni Butturini; Giovanni Capretti; Riccardo Casadei; Bjørn Edwin; Anouk M L H Emmen; Alessandro Esposito; Massimo Falconi; Bas Groot Koerkamp; Tobias Keck; Ruben H J de Kleine; Dyre B Kleive; Arto Kokkola; Daan J Lips; Sanne Lof; Misha D P Luyer; Alberto Manzoni; Ravi Marudanayagam; Matteo de Pastena; Nicolò Pecorelli; John N Primrose; Claudio Ricci; Roberto Salvia; Per Sandström; Frederique L I M Vissers; Ulrich F Wellner; Alessandro Zerbi; Marcel G W Dijkgraaf; Marc G Besselink; Mohammad Abu Hilal; European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS)

doi:10.1016/j.lanepe.2023.100673

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial

Lancet Reg Health Eur. 2023 Jul 6:31:100673. doi: 10.1016/j.lanepe.2023.100673. eCollection 2023 Aug.

Authors

Maarten Korrel^{1

2

3}, Leia R Jones^{1

2

3}, Jony van Hilst^{2

3

4}, Gianpaolo Balzano⁵, Bergthor Björnsson⁶, Ugo Boggi⁷, Svein Olav Bratlie⁸, Olivier R Busch^{2

3}, Giovanni Butturini⁹, Giovanni Capretti^{10

11}, Riccardo Casadei¹², Bjørn Edwin¹³, Anouk M L H Emmen^{1

2

3}, Alessandro Esposito¹⁴, Massimo Falconi⁵, Bas Groot Koerkamp¹⁵, Tobias Keck¹⁶, Ruben H J de Kleine¹⁷, Dyre B Kleive¹⁸, Arto Kokkola¹⁹, Daan J Lips²⁰, Sanne Lof^{2

21}, Misha D P Luyer²², Alberto Manzoni¹, Ravi Marudanayagam²³, Matteo de Pastena¹⁴, Nicolò Pecorelli⁵, John N Primrose²¹, Claudio Ricci¹², Roberto Salvia¹⁴, Per Sandström⁶, Frederique L I M Vissers^{2

3}, Ulrich F Wellner¹⁶, Alessandro Zerbi^{10

11}, Marcel G W Dijkgraaf^{24

25}, Marc G Besselink^{2

3}, Mohammad Abu Hilal^{1

21}; European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS)

Collaborators

European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS):
Adnan Alseidi, Constanza Aquilano, Johanna Arola, Denise Bianchi, Rachel Brown, Daniela Campani, Joanne ChinAleong, Jerome Cros, Lyubomira Dimitrova, Claudio Doglioni, Safi Dokmak, Russell Dorer, Michael Doukas, Jean Michel Fabre, Giovanni Ferrari, Viacheslay Grinevich, Stefano Gobbo, Thilo Hackert, Marius van den Heuvel, Clement Huijsentruijt, Mar Iglesias, Casper Jansen, Igor Khatkov, David Kooby, Marco Lena, Claudio Luchini, Krishna Menon, Patrick Michenet, Quintus Molenaar, Anna Nedkova, Andrea Pietrabissa, Mihaela Raicu, Rushda Rajak, Branislava Rankovic, Aniko Rendek, Benjamin Riviere, Antonio Sa Cunha, Olivier Saint Marc, Patricia Sanchez Velazquez, Donatella Santini, Aldo Scarpa, Mylene Sebagh, Donald Sears, Mihir Shah, Zahir Soonawalla, Paola Spaggiari, Lars Tharun, Tore Tholfsen, Ales Tomazic, Alessandro Vanoli, Caroline Verbeke, Joanne Verheij, Moritz Von Winterfeld, Roeland de Wilde, Vincent Yip, Yoh Zen

Affiliations

¹ Department of General Surgery, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy.
² Amsterdam UMC, University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands.
³ Cancer Center Amsterdam, the Netherlands.
⁴ Department of Surgery, OLVG Hospital, Amsterdam, the Netherlands.
⁵ Department of Surgery, San Raffaele Hospital IRCCS, Università Vita-Salute, Milan, Italy.
⁶ Departments of Surgery, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁷ Department of Surgery, Universitá di Pisa, Pisa, Italy.
⁸ Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁹ Department of Surgery, Pederzoli Hospital, Peschiera, Italy.
¹⁰ Pancreatic Surgery, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.
¹¹ IRCCS Humanitas Research Hospital, Rozzano, Italy.
¹² Division of Pancreatic Surgery IRCCS, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
¹³ The Intervention Center, Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁴ Department of General and Pancreatic Surgery - Pancreas Institute, University Hospital of Verona, Verona, Italy.
¹⁵ Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
¹⁶ Department of Surgery, UKSH Campus Lübeck, Lübeck, Germany.
¹⁷ Department of Surgery, University Medical Centre Groningen, Groningen, the Netherlands.
¹⁸ Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹⁹ Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
²⁰ Department of Surgery, Medisch Spectrum Twente, Enschede, the Netherlands.
²¹ Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
²² Department of Surgery, Catharina Ziekenhuis, Eindhoven, the Netherlands.
²³ Department of HPB Surgery, University Hospital Birmingham, Birmingham, UK.
²⁴ Amsterdam UMC, University of Amsterdam, Department of Epidemiology and Data Science, Amsterdam, the Netherlands.
²⁵ Amsterdam Public Health, Methodology, Amsterdam, the Netherlands.

Abstract

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking.

Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of -7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265).

Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI -6.2 to 13.6%; p_{non-inferiority} = 0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0-30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5-5.5] vs 5 [95% CI 4.7-5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67-1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group.

Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer.

Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Keywords: Distal pancreatectomy; Minimally invasive surgery; Pancreatic ductal adenocarcinoma.